Nuclear factor-kappaB sensitizes to benzyl isothiocyanate-induced antiproliferation in p53-deficient colorectal cancer cells.
Nuclear factor-kappaB sensitizes to benzyl isothiocyanate-induced antiproliferation in p53-deficient colorectal cancer cells.
复制标题
DOI：
10.1038/cddis.2014.495
复制
发表时间：
2014-11-20
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
异硫氰酸苄基（Benzyl isothiocyanate， BITC）是一种从十字花科蔬菜中提取的膳食异硫氰酸盐，可抑制结直肠癌细胞的增殖，大多数结直肠癌细胞由于大肠腺瘤性息肉病基因突变或β-catenin本身突变而过度表达β-catenin。由于核因子-κB （NF-κB）在炎症细胞模型中可能是BITC信号传导的靶点，我们假设它也参与BITC抑制结直肠癌细胞的增殖。sirna介导的NF-κB p65亚基的下调显著降低了p53肿瘤抑制蛋白突变的人结直肠癌HT-29细胞的BITC敏感性。BITC处理HT-29细胞可诱导i -κB激酶、i -κB -α和p65磷酸化、i -κB -α降解、p65向细胞核易位以及NF-κB转录活性上调。BITC还减少了β-catenin与cyclin D1启动子正顺式元件的结合，从而抑制了β-catenin依赖性cyclin D1的转录，这可能是通过p65和β-catenin之间的直接相互作用实现的。sirna介导的p65敲低证实p65负性影响cyclin D1的表达。另一方面，当使用BITC处理具有野生型p53的人类结直肠癌HCT-116细胞时，p65向细胞核的易位被抑制而不是增强。p53敲除以p65依赖的方式增加HCT-116细胞的BITC敏感性，提示p53负向调节p65依赖效应。综上所述，这些结果表明BITC是一种新型的抗增殖药物，可以调节p53缺失的结直肠癌细胞中的NF-κB通路。
Benzyl isothiocyanate (BITC), a dietary isothiocyanate derived from cruciferous vegetables, inhibits the proliferation of colorectal cancer cells, most of which overexpress β-catenin as a result of mutations in the genes for adenomatous polyposis coli or mutations in β-catenin itself. Because nuclear factor-κB (NF-κB) is a plausible target of BITC signaling in inflammatory cell models, we hypothesized that it is also involved in BITC-inhibited proliferation of colorectal cancer cells. siRNA-mediated knockdown of the NF-κB p65 subunit significantly decreased the BITC sensitivity of human colorectal cancer HT-29 cells with mutated p53 tumor suppressor protein. Treating HT-29 cells with BITC induced the phosphorylation of IκB kinase, IκB-α and p65, the degradation of IκB-α, the translocation of p65 to the nucleus and the upregulation of NF-κB transcriptional activity. BITC also decreased β-catenin binding to a positive cis element of the cyclin D1 promoter and thus inhibited β-catenin-dependent cyclin D1 transcription, possibly through a direct interaction between p65 and β-catenin. siRNA-mediated knockdown of p65 confirmed that p65 negatively affects cyclin D1 expression. On the other hand, when human colorectal cancer HCT-116 cells with wild-type p53 were treated with BITC, translocation of p65 to the nucleus was inhibited rather than enhanced. p53 knockout increased the BITC sensitivity of HCT-116 cells in a p65-dependent manner, suggesting that p53 negatively regulates p65-dependent effects. Together, these results identify BITC as a novel type of antiproliferative agent that regulates the NF-κB pathway in p53-deficient colorectal cancer cells.
登录
查看更多内容
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
10.5
作者：
Chien, Yuchen;Scuoppo, Claudio;Lowe, Scott W.
通讯作者：
Lowe, Scott W.
影响因子：
5.3
作者：
Hulit, J;Wang, CG;Pestell, RG
通讯作者：
Pestell, RG
影响因子：
4.6
作者：
Khor, Tin Oo;Cheung, William Ka Lung;Kong, Ah-Ng Tony
通讯作者：
Kong, Ah-Ng Tony
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW